The overall goals of this proposal are to elucidate the mechanisms underlying protection against cancer in three experimental systems; to identify possible novel mechanisms; and to apply this information to the development of effective chemoprotective agents. Project A is concerned with the identification of the common signal whereby chemoprotectors induce detoxifying enzymes (glutathione S-transferases; NAD(P)H:quinone reductase) that inactivate ultimate carcinogens. For this project; (a) a variety of oxidation-reduction-labile compounds, and agents that generate or inactivate active oxygen species will be examined, and (b) the genetic controlling elements involved in regulation of induction will be analyzed. In project B, parallel studies are designed (a) to clarify the role of direct (chemical) and indirect (metabolic) generation of free radicals by tumor promoters in mouse epidermis; (b) to examine chemical and enzymatic generators of reactive oxygen species as mimics of tumor promotion; and (c) to define the role of reduction potential in the mechanism of inhibition of tumor promotion by antioxidants. In addition, studies are proposed on the modulation of expression of superoxide dismutase (an important intracellular oxygen radical detoxifier) in mouse skin during chronic exposure to tumor promoters. In project C an analysis of the powerful antiproliferative, antidifferentiational and anticarcinogenic actions of the abundant endogenous steroid, dehydroepiandrosterone (DHEA), will be undertaken. For this project: (a) the role of the inhibition of glucose-6- phosphate dehydrogenase in these effects of DHEA will be analyzed in 3T3-L1 preadipocyte clones; (b) rapid enzymatic methods will be developed for measuring DHEA and its conjugates (including hitherto unidentified conjugates) in human plasma; (c) the possibility that low levels of DHEA (and its conjugates) predict increased risk for the development of cancer will then be tested by measuring these substances in selected samples from a unique human serum bank in which the development of cancer among the donors is being carefully monitored; (d) a pharmacokinetics trial of oral DHEA in man is proposed to establish the feasibility of elevating plasma levels of aging humans to values prevailing in young adults. Such information is basic to the design of chemoprotection trials with DHEA in populations at high risk for the development of cancer.